Formation of STAT5/PPARgamma transcriptional complex modulates angiogenic cell bioavailability in diabetes.
OBJECTIVE
Circulating angiogenic cells (CACs) expansion is a multistage process requiring sequential activation of transcriptional factors, including STAT5. STAT5, in concert with peroxisome proliferator-activated receptors (PPARs), seems to induce discrete biological responses in different tissues. In the present study we investigated the role of STAT5 and PPARgamma in regulating CAC expansion in normal and diabetic settings.


RESULTS
Normal and diabetic CACs were used. siRNA technology, EMSA, and chromatin immunoprecipitation (ChIP) assay as well as site-directed mutagenesis of the STAT5 response element in the PPARgamma promoter enabled us to demonstrate that STAT5 transcriptional activity controls PPARgamma expression. Moreover, FACS analysis, coimmunoprecipitation experiments, and ChIP assay revealed that a STAT5/PPARgamma transcriptional complex controls cyclin D1 expression and CAC progression into the cell-cycle. Conversely, PPARgamma agonists, by preventing the expression of STAT5 and the formation of the STAT5/PPARgamma heterodimeric complex failed to promote CAC expansion. Finally, we demonstrated that diabetic CAC functional capability can be recovered by molecules able to activate the STAT5/PPARgamma transcriptional complex.


CONCLUSIONS
Our data identify the STAT5/PPARgamma heterodimers as landmark of CAC expansion and provide evidences for a mechanism that partially rescues CAC bioavailability in diabetic setting.
Dentelli
Patrizia
P
Department of Internal Medicine, University of Torino, Corso Dogliotti 14, 10126, Torino, Italy.
Trombetta
Antonella
A
Togliatto
Gabriele
G
Zeoli
Annarita
A
Rosso
Arturo
A
Uberti
Barbara
B
Orso
Francesca
F
Taverna
Daniela
D
Pegoraro
Luigi
L
Brizzi
Maria Felice
MF
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009389:Neovascularization, Pathologic / Q000235:genetics*; D047495:PPAR gamma / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic
D047495:PPAR gamma; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; D012313:RNA; D008156:Luciferases